Process for producing packing for resolving optical isomers

ABSTRACT

The present invention provides a production method with which a porous carrier can be allowed to evenly carry a polysaccharide derivative. That is, the present invention provides a method of producing an enantiomeric isomer-separating filler, including bringing a porous carrier and a solution of a polysaccharide derivative into contact with each other through a stirring operation in a stirring device, to allow the porous carrier to carry an optically active polymer compound, in which: a two-axis vertical stirring device is used as the stirring device; and the porous carrier is allowed to carry the polysaccharide derivative in a carrying amount of 23 mass % or more.

TECHNICAL FIELD TO WHICH THE INVENTION BELONGS

The present invention relates to a method of producing an enantiomericisomer-separating filler.

PRIOR ART

Conventionally, separation technologies including liquid chromatography,supercritical chromatography, and gas chromatography as a method ofisolating a desired component from an isomer mixture or the likecontaining two or more components have widely been used for variouskinds of analyses such as environmental analysis, metabolic analysis,and impurity analysis.

Those separation technologies are considered to be a kind of analysistechnology, but have an aspect different from a technology for isolatinga particular component in large quantities at a high purity from amixture containing multiple components. In other words, the concept of“separation” in the field of analysis technology means separating eachcomponent from a mixture containing multiple components at a necessarylevel of purity for identifying each component. The term “separation”does not mean bulk separation and prevention of contamination ofimpurities.

On the other hand, in the fields of separation of physiologically activesubstances and separation of optically active antipodes, “separation”demands the separation of a single substance at a high purity. Thereforethe separation of, for example, an optically active substance at a highpurity in large quantities cannot be achieved by means of a separationtechnology at a chemical analysis level.

Incidentally, simulated moving bed chromatographic separation methodshave been conducted to achieve separation on an industrial scale at ahigh purity. Under such circumstances, the demand for enantiomericisomer-separating fillers has increased, and a technology with which anenantiomeric isomer-separating filler having stable quality can beproduced on a large scale has been required.

Examples of a method of producing an enantiomeric isomer-separatingfiller include: a method proposed by Okamoto et al. (Y. Okamoto, M.Kawashima and K. Hatada, J. Am. Chem. 106, 5357, 1984), in which silicagel is immersed in a solution of polysaccharide derivatives and thesolvent is distilled off; an impact method in high speed flow asdisclosed in JP 3-2009 B, and a method of preparing a carrier byspraying as disclosed in JP 63-84626 A.

With each of those methods, an enantiomeric isomer-separating fillerhaving separating performance that is satisfactory to some extent can beproduced when further testing is performed at a laboratory level atwhich some hundred grams of an enantiomeric isomer-separating filler areproduced.

However, when a researcher tried to produce an enantiomericisomer-separating filler on an increased scale, in an amount of 1 kg toseveral ten kilograms, it turned out that an enantiomericisomer-separating filler having excellent separating performance couldnot always be obtained by this method. For example, in an enantiomericisomer-separating filler obtained by means of any one of those methods,to allow the carrier to evenly carry a polysaccharide derivative or thelike, and to allow the inner walls of pores of the carrier to carry thepolysaccharide derivative or the like are difficult. Besides, after thecarrier is allowed to carry the polysaccharide derivative or the like,the solvent remaining in the carrier is uneven. Further, particles areformed through agglomeration of the polysaccharide derivative or thelike which is not carried by the carrier. Those factors lower theseparating performance to such an extent that the obtained filler cannotpractically be used.

Also, when a column is filled with an enantiomeric isomer-separatingfiller and enantiomeric isomers are separated, a pressure loss ispreferably low in order to let a liquid, gas, or super critical fluidpass through. In view of the above, generally, a method that possiblybreaks the carrier cannot be employed. Even though the above mentionedmethod can provide an excellent filler in laboratory size, such a methodcannot always provide good results with an enantiomericisomer-separating filler produced in a large size for industrialproduction. Because a mixing/stirring power for a carrier and apolysaccharide derivative or the like becomes larger or changes in othervarious conditions are involved.

DISCLOSURE OF THE INVENTION

A purpose of the present invention is to provide a method of producingan enantiomeric isomer-separating filler which has high separatingperformance, which can be applied to levels ranging from a laboratorylevel to an industrial production level, and which is particularlysuitable for an enantiomeric isomer-separating filler for simulatedmoving bed chromatography.

The invention according to claim 1 provides, as means for achieving theobject, a method of producing an enantiomeric isomer-separating filler,including bringing a porous carrier and a solution of an opticallyactive polymer compound into contact with each other through a stirringoperation in a stirring device, to allow the porous carrier to carry thesolution of the optically active polymer compound, in which:

-   -   a two-axis vertical stirring device is used as the stirring        device; and    -   the porous carrier is allowed to carry the optically active        polymer compound in a carrying amount of 23 mass % or more.

In bringing the porous carrier and the solution of the optically activepolymer compound into contact with each other in the two-axis verticalstirring device, any one of a method in which feeding of the porouscarrier and the solution of the optically active polymer compound isperformed before stirring of them with the two-axis vertical stirringdevice, a method in which the feeding and the stirring are performed intandem with each other, and a method in which the stirring is startedbefore the feeding can be applied to the order in which the feeding andthe stirring are performed.

The carrying amount of the optically active polymer compound is a ratioof the compound in the enantiomeric isomer-separating filler, andsubstantially has a value determined from the following equation: themass of the optically active polymer compound/(the mass of the porouscarrier+the mass of the optically active polymer compound)×100.

The invention according to claim 2 provides, as another means forachieving the object, a method of producing an enantiomericisomer-separating filler, including bringing a porous carrier and asolution of an optically active polymer compound into contact with eachother through a stirring operation in a stirring device, to allow theporous carrier to carry the solution of the optically active polymercompound, in which:

-   -   a two-axis vertical stirring device is used as the stirring        device;    -   a first step involving: feeding the porous carrier into the        two-axis vertical stirring device; adding part of the solution        of the optically active polymer compound with a required amount        being divided into multiple fractions; and allowing the porous        carrier to carry the optically active polymer compound through a        stirring operation of the two-axis vertical stirring device, and        a second step involving drying the porous carrier carrying the        optically active polymer compound to remove a solvent are        performed; and    -   a combination of the first step and the second step is repeated        a plurality of times by using a residual solution of the        optically active polymer compound, to thereby allow the porous        carrier to carry the optically active polymer compound.

In the filler, the porous carrier (such as silica gel) carrying theoptically active polymer compound (such as a polysaccharide derivative)has many voids (openings). Since an enantiomeric isomer to be separatedis adsorbed by the polymer compound present in the voids, a ratio of thevoids plays an important role in specifying the carrying amount andseparating performance of the polymer compound. The ratio of the voidswith respect to the entire porous carrier is expressed as a voidvolume/the volume of the porous carrier (hereinafter, the ratiodetermined from the equation is referred to as a “void ratio”). When aporous carrier having a predetermined void ratio is allowed to carry anoptically active polymer compound, the optically active polymer compoundadheres to the voids, so the void volume reduces to change the voidratio. At this time, as described above, the control of the void volume,the void ratio, and the carrying amount of the polymer compound can befacilitated by repeating the combination of the first step and thesecond step plural times. As a result, the control of the separatingperformance can be facilitated, which is preferable.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a drawing showing a revolution trajectory of a stirring bladein a two-axis vertical stirring device.

FIG. 2 is a drawing showing another revolution trajectory of thestirring blade in the two-axis vertical stirring device.

FIG. 3 is a conceptual drawing showing an example of a simulated movingbed mode.

FIG. 4 is a conceptual drawing showing another example of the simulatedmoving bed mode.

FIG. 5 shows a chromatogram using a column of Example 1 obtained inApplied Example 1.

FIG. 6 shows a chromatogram using a column of Example 2 obtained inApplied Example 1.

FIG. 7 shows a chromatogram using a column of Example 3 obtained inApplied Example 1.

FIG. 8 shows a chromatogram using a column of Example 4 obtained inApplied Example 1.

FIG. 9 shows a chromatogram using a column of Example 5 obtained inApplied Example 1.

FIG. 10 shows a chromatogram using a column of Comparative Example 1obtained in Applied Example 1.

FIG. 11 is a conceptual drawing showing a continuous liquidchromatograph-separation device of a small-simulated moving bed mode.

DETAILED DESCRIPTION OF THE INVENTION

The production method of the present invention includes bringing aporous carrier and a solution of an optically active polymer compoundinto contact with each other under stirring in a two-axis verticalstirring device, to allow the porous carrier to carry the solution ofthe optically active polymer compound.

In bringing the porous carrier and the solution of the optically activepolymer compound into contact with each other in the two-axis verticalstirring device, any one of:

-   -   (a) a method in which the porous carrier and the solution or        dispersion of the optically active polymer compound are fed into        the two-axis vertical stirring device before they are stirred        with the stirring device (however, the order in which the porous        carrier and the solution are fed and a method of feeding them        can be appropriately modified);    -   (b) a method in which the porous carrier is placed into the        two-axis vertical stirring device, and the optically active        polymer compound is placed in tandem with stirring with the        stirring device (however, the order in which the porous carrier        and the compound are placed and a method of placing them can be        appropriately modified); and    -   (c) a method in which stirring with the two-axis vertical        stirring device is started, and then the porous carrier and the        solution or dispersion of the optically active polymer compound        are placed into the two-axis vertical stirring device (however,        the order in which the porous carrier and the solution or        dispersion are placed and a method of placing them can be        appropriately modified) can be applied. However, in the present        invention, the method (b) is preferably adopted in order to        enhance carrying performance of the porous carrier with respect        to the optically active polymer compound.

The two-axis vertical stirring device is equipped with: a stirring tankfor accommodating the porous carrier and the solution of the opticallyactive polymer compound; and two stirring means (stirring blades)capable of stirring the inside of the tank. The stirring device may beequipped with a heating device (such as a heating jacket) as required.

The two stirring blades are preferably ones which revolve while rotatingtogether. The rotation directions of the two stirring blades may beidentical to or different from each other. The revolution of each of thetwo stirring blades is preferably set to draw a hypocycloid curve shownin FIG. 1 or a hypercyclone curve shown in FIG. 2.

When the two stirring blades operate as described above, the carryingperformance of the porous carrier with respect to the optically activepolymer compound (such as evenness of carrying or an increase inloading) can be enhanced. At the same time, the optically active polymercompound can be prevented from becoming a lump (particulate mass).Therefore, the porous carrier can be allowed to carry substantially atotal amount of the optically active polymer compound used. Inparticular, when the revolution trajectory of each of the two stirringblades is a hypocycloid curve or a hypercyclone curve, there is no deadpoint in the stirring tank, and substances to be mixed (the porouscarrier and the optically active polymer compound) which are building upwithout being stirred are eliminated. As a result, the carryingperformance can be further enhanced.

Each of the two stirring blades may be a curved stirring rod or a curvedstirring ring. When each of the two stirring blades is a curved stirringrod, the rod is preferably a hook-shaped rod or an anchor-typehook-shaped rod.

When the two stirring blades of those types are used, the stirringblades serve to press the substances to be mixed against each other orto knead them. As a result, when the substances are heated with aheating jacket, replacement of the substances at a position in contactwith the heating jacket is smoothly performed, whereby an adverse effectof thermal hysteresis is prevented. The emergence of a lump is alsoprevented.

The capacity of the stirring tank can be appropriately set in accordancewith the amounts of the porous carrier and the solution of the opticallyactive polymer compound in a range from a laboratory scale to anindustrial production scale. For example, the capacity can be set in therange of 0.03 to 3 m³.

A porous organic carrier or a porous inorganic carrier can be used asthe porous carrier. Of those, a porous inorganic carrier is preferable.

Examples of appropriate porous organic carriers include polymersubstances made of polystyrene, polyacrylamide, polyacrylate, and thelike. Examples of appropriate porous inorganic carriers include silica,alumina, magnesia, glass, kaolin, titanium oxide, silicate, andhydroxyapatite. However, silica gel is particularly preferable. Whensilica gel is used, its surface is desirably subjected to silanetreatment (silane treatment using aminopropylsilane), plasma treatment,or the like in order to eliminate the influence of silanol remaining onthe silica gel surface and to enhance an affinity for the opticallyactive polymer compound. However, no problems occur even when thesurface is subjected to no treatment.

The porous carrier, particularly silica gel, has a particle sizepreferably in the range of 1 to 300 μm, more preferably in the range of15 to 100 μm, still more preferably in the range of 20 to 50 μm, and anaverage pore size preferably in the range of 200 to 8,000 Å, morepreferably in the range of 200 to 4,000 Å, still more preferably in therange of 300 to 2,000 Å. The particle size of the porous carrier issubstantially the particle size of a filler.

An average pore size of the porous carrier in the above range ispreferable because the solution of the optically active polymer compoundis sufficiently immersed in pores and the optically active polymercompound tends to evenly adhere to the inner walls of the pores.Furthermore, the pores are not closed, so the pressure loss of thefiller can be kept at a low level.

A polysaccharide derivative is preferably used as the optically activepolymer compound. A polysaccharide, from which the polysaccharidederivative is derived, may be a synthetic polysaccharide, a naturalpolysaccharide or a natural product-modified polysaccharide. Anyone maybe used as long as it is optically active. One having a high regularityof form of bonding is desirably used.

Examples of the polysaccharide include β-1,4-glucan (cellulose),α-1,4-glucan (amylose, amylopectin), α-1,6-glucan (dextran),β-1,6-glucan (pustulan), β-1,3-glucan (for example, curdlan,schizofillan, etc.), α-1,3-glucan, β-1,2-glucan (Crown Gallpolysaccharide), β-1,4-galactan, β-1,4-mannan, α-1,6-mannan,β-1,2-fructan (inulin), β-2,6-fructan (levan), β-1,4-xylan, β-1,3-xylan,β-1,4-chitosan, α-1,4-N-acetylchitosan (chitin), pullulan, agarose,alginic acid, etc. as well as amylose-containing starch.

Among these, cellulose, amylose, β-1,4-xylan, β-1,4-chitosan, chitin,β-1,4-mannan, inulin, curdlan, etc., from which high puritypolysaccharides are readily available, are preferred, with cellulose andamylose being particularly preferred.

The number average degree of polymerization (average number of pyranoseor furanose ring contained in one molecule) of these polysaccharides ispreferably 5 or more, more preferably 10 or more. There is no particularupper limit in the number average degree of polymerization but it isdesirably 1,000 or less in consideration of ease of handling. It is morepreferably 5 to 1,000, further more preferably 10 to 1,000, andparticularly preferably 10 to 500.

Each of polysaccharide derivatives obtained by bonding the part or wholeof the hydroxyl groups of the above polysaccharides with compoundshaving functional groups capable of reacting with hydroxyl groupsthrough ester bonds, urethane bonds, ether bonds, and the like can beused as the polysaccharide derivative.

Examples of a compound having a functional group capable of reactingwith a hydroxyl group, which may be any one as long as the compound hasa leaving group, include an isocyanic acid derivative, a carboxylicacid, an ester, an acid halide, an acid amide compound, a halogencompound, an aldehyde, and an alcohol. Aliphatic, alicyclic, aromatic,and heteroaromatic compounds of the above compounds can also be used.

Examples of a particular preferable polysaccharide derivative include apolysaccharide ester derivative and a polysaccharide carbamatederivative. Examples of the polysaccharide ester derivative and thepolysaccharide carbamate derivative include a compound obtained bysubstituting at least one of the atomic groups represented by thefollowing formulae for the part or whole of hydrogen atoms on hydroxylgroups or on amino groups of a polysaccharide.

(In the formulae, R represents an aromatic hydrocarbon group which maycontain a hetero atom, and may be unsubstituted or substituted by atleast one group selected from the group consisting of an alkyl grouphaving 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbonatoms, an alkylthio group having 1 to 12 carbon atoms, a cyano group, ahalogen atom, an acyl group having 1 to 8 carbon atoms, analkoxycarbonyl group having 1 to 8 carbon atoms, a nitro group, an aminogroup, and an alkylamino group having 1 to 8 carbon atoms.

Particularly preferable examples of the aromatic hydrocarbon groupinclude a phenyl group, a naphthyl group, a phenanthryl group, ananthracyl group, an indenyl group, a furyl group, a thionyl group, apyryl group, a benzofuryl group, a benzothionyl group, an indyl group, apyridyl group, a pyrimidyl group, a quinolyl group, and an isoquinolylgroup. Of those, a phenyl group, a naphthyl group, a pyridyl group, andthe like are preferable. A halogenated phenyl group and an alkylphenylgroup are particularly preferable.

X represents a hydrocarbon group having 1 to 4 carbon atoms which maycontain a double bond or a triple bond. Examples of X include amethylene group, a methylmethylene group, an ethylene group, anethylidene group, an ethenylene group, an ethynylene group, a 1,2- or1,3-propylene group, and a 1,1- or 2,2-propyridine group.]

The polysaccharide carbamate derivative can be obtained by reacting anisocyante represented by the below shown formula with a polysaccharide.The polysaccharide ester derivative can be obtained by reacting an acidchloride represented by the below shown formula with a polysaccharide.

(In the formulae, R and X each have the same meaning as above.)

An introducing ratio of a substituent into a polysaccharide derivativeis preferably in the range of 10% to 100%, more preferably in the rangeof 30% to 100%, still more preferably in the range of 80% to 100%. Anintroducing ratio of 10% or more is preferable because an opticalresolution ability increases. An introducing ratio of 30% or more ispreferable because sufficient separating performance can be achievedregardless of the type and concentration of a mixture of enantiomericisomers to be subjected to optical resolution. An introducing ratio of80% or more is particularly preferable because a particle excellent inenantiomeric isomer separating performance can be obtained. Theintroducing ratio of a substituent can be determined by investigatingchanges in carbon, hydrogen, and nitrogen before and after substituentintroduction through elemental analysis.

The solution or dispersion of the optically active polymer compound iscomposed of a polymer compound such as any one of the abovepolysaccharide derivatives and an organic solvent.

Examples of the organic solvent include: ketones such as acetone andmethyl ethyl ketone; aromatic carboxylic acid alkyl esters including abenzoic acid alkyl ester such as methyl benzoate; and halogen compoundssuch as methylacetamide, methylene chloride, and chloroform.

A mixing ratio between the optically active polymer compound and theorganic solvent is preferably 300 to 10,000 parts by mass, morepreferably 300 to 1,000 parts by mass of the organic solvent withrespect to 100 parts by mass of the optically active polymer compound.

A ratio between the porous carrier and the solution or dispersion of theoptically active polymer compound is preferably 100 to 500 parts bymass, more preferably 100 to 300 parts by mass of the solution ordispersion of the optically active polymer compound with respect to 100parts by mass of the porous carrier.

A total volume of the porous carrier and the solution or dispersion ofthe optically active polymer compound with respect to the stirring tankcapacity of the two-axis vertical stirring device is such that the totalvolume of the porous carrier and the solution or dispersion of theoptically active polymer compound is preferably 0.1 to 0.8 m³, morepreferably 0.2 to 0.5 m³ with respect to the stirring tank capacity of 1m³.

A temperature condition at the time of stirring is preferably in therange of room temperature to 80° C., more preferably in the range ofroom temperature to 60° C.

An operation condition for the stirring blades varies depending onparameters such as: the capacity of the stirring tank; the amounts ofthe porous carrier and the solution or dispersion of the opticallyactive polymer compound used; the shapes of the stirring blades; therotational speeds of the stirring blades; and the rotation trajectoriesof the stirring blades. However, when the numerical ranges of the aboveparameters are satisfied, stirring for about 10 to 300 minutes allowsthe porous carrier to carry the optically active polymer compound.

When the porous carrier and the solution or dispersion of the opticallyactive polymer compound are stirred in the two-axis vertical stirringdevice, they may be irradiated with light, radiation such as a γ ray, oran electromagnetic wave such as a microwave to enhance a bonding forcebetween the porous carrier and the optically active polymer compound.

The above stirring processing using the two-axis vertical stirringdevice allows the porous carrier to carry the optically active polymercompound. The carrying state varies depending on a combination of theporous carrier and the optically active polymer compound, and rangesfrom a state where the optically active polymer compound merely adheresto the porous carrier to a state where the porous carrier and theoptically active polymer compound are chemically bound to each other.Therefore, as described above, the porous carrier and the opticallyactive polymer compound may be irradiated with light, radiation such asa γ ray, or an electromagnetic wave such as a microwave to enhance thebonding force between the porous carrier and the optically activepolymer compound as required.

After the completion of the stirring processing, the organic solvent isremoved through drying processing, and furthermore, as required,classification processing such as a vibrating screen, a cyclone, airclassification, or wet classification, washing processing, and dryingprocessing can be performed.

The above production method can provide an enantiomericisomer-separating filler in which the porous carrier is allowed to carrythe optically active polymer compound in a carrying amount of 23 mass %or more.

The carrying amount as used herein is represented by a ratio of theweight of the polysaccharide derivative to the weight of the filler. Thecarrying amount of the polysaccharide derivative on the carrier ispreferably 23 mass % or more with respect to the carrier. The carryingamount is more preferably 27 mass % or more from the view point ofproductivity. There is no particular technical upper limit of thecarrying amount. A carrying amount of 60 mass % or less is preferablebecause no reduction in separation efficiency due to a reduction innumber of stages occurs. The carrying amount is particularly preferablyin the range of 27 mass % to 45 mass %.

In the production method of the present invention, as described above,the method (b) is preferably applied in bringing the porous carrier andthe solution of the optically active polymer compound into contact witheach other in the two-axis vertical stirring device. However, asdescribed below, it is particularly preferable to modify the method (b)for achieving the object of the present invention.

First, the porous carrier is fed into the two-axis vertical stirringdevice, and part of the solution or dispersion of the optically activepolymer compound with a required amount being divided into multiplefractions is added. At this time, the number of divisions, which is notparticularly limited, is preferably 2 to 6, more preferably 2 to 4.

Next, the porous carrier is allowed to carry the optically activepolymer compound through a stirring operation of the two-axis verticalstirring device.

Then, the porous carrier carrying the optically active polymer compoundis dried to remove a solvent.

The combination of the above steps is counted as one process. Theprocess is repeated a plurality of times, preferably 2 to 6 times, morepreferably 2 to 4 times. The amounts of the solution or dispersion ofthe optically active polymer compound to be added for the respectivetimes may be the same or different.

The enantiomeric isomer-separating filler obtained by means of theproduction method of the present invention is preferably used for aseparation column of simulated moving bed chromatography intended toobtain several milligrams to several kilograms of an optically activesubstance.

The column has a ratio L/D of the length (L) of one column to the innerdiameter (D) of the column preferably in the range of 0.01 to 100, morepreferably in the range of 0.01 to 60, still more preferably in therange of 0.01 to 30.

Adsorption and separation by means of simulated moving bedchromatography are carried out by continuously circulating an adsorptionoperation, a condensation operation, a desorption operation, and adesorbed liquid collection operation described below as basicoperations.

(1) Adsorption Operation

A mixture of enantiomeric isomers contacts an enantiomericisomer-separating filler. Then, an enantiomeric isomer that is easilyadsorbed (strong adsorption component) is adsorbed, while otherenantiomeric isomer that is hardly adsorbed (weak adsorption component)is collected as a raffinate flow together with a desorbed liquid.

(2) Condensation Operation

The enantiomeric isomer-separating filler that has adsorbed the strongadsorption component is allowed to contact part of an extract to bedescribed later, so the weak adsorption component remaining on theenantiomeric isomer-separating filler is expelled to condense the strongadsorption component.

(3) Desorption Operation

The enantiomeric isomer-separating filler containing the condensedstrong adsorption component is allowed to contact the desorbed liquid,so the strong adsorption component is expelled from the enantiomericisomer-separating filler to be collected as an extract flow accompanyingthe desorbed liquid.

(4) Desorbed Liquid Collection Operation

The enantiomeric isomer-separating filler adsorbing substantially onlythe desorbed liquid contacts part of the raffinate flow, so part of thedesorbed liquid in the enantiomeric isomer-separating filler iscollected as a desorbed liquid collection flow.

In the adsorption and separation by means of simulated moving bedchromatography, a total number of columns to be used for performing theadsorption operation, the condensation operation, the desorptionoperation, and the desorbed liquid collection operation described above(each of the columns should have the above L/D ratio) is preferably 4 to32, more preferably 4 to 12, still more preferably 4 to 8.

Hereinafter, a simulated moving bed chromatography method will bedescribed with reference to the drawings. FIG. 3 is a schematic drawingshowing an example of a simulated moving bed according to the presentinvention. FIG. 4 is a schematic drawing showing another example of thesimulated moving bed according to the present invention. In FIG. 3, theinside of a packed bed serving as a main portion of the simulated movingbed is divided into 12 unit packed beds. In FIG. 4, the inside isdivided into 8 unit packed beds. However, the number and sizes of theunit packed beds depend on factors such as the composition and flow rateof an enantiomeric isomer mixture-containing liquid, a pressure loss,and the size of the device, and are not limited.

In FIG. 3, reference numerals 1 to 12 each denote a chamber (adsorptionchamber) filled with a filler, and the chambers are coupled to oneanother. Reference numeral 13 denotes a desorbed liquid supplying line;14, an extract drawing line; 15, an enantiomeric isomer-containingliquid supplying line; 16, a raffinate drawing line; 17, a recycle line;and 18, a pump.

In an arrangement state of the adsorption chambers 1 to 12 and the lines13 to 16 shown in FIG. 3, the adsorption chambers 1 to 3 perform thedesorption operation, the adsorption chambers 4 to 6 perform thecondensation operation, the adsorption chambers 7 to 9 perform theadsorption operation, and the adsorption chambers 10 to 12 perform thedesorbed liquid collection operation. In such a simulated moving bed,each of the supplying lines and the drawing lines is moved by oneadsorption chamber in a liquid flowing direction through a bulboperation every predetermined time period. Accordingly, in the nextarrangement state of the adsorption chambers, the adsorption chambers 2to 4 perform the desorption operation, the adsorption chambers 5 to 7perform the condensation operation, the adsorption chambers 8 to 10perform the adsorption operation, and the adsorption chambers 11, 12,and 1 perform the desorbed liquid collection operation. Such anoperation is performed successively, whereby processing of separatingthe mixture of enantiomeric isomers can be continuously and efficientlyachieved.

In addition, in an arrangement state of the adsorption chambers 1 to 8and the lines 13 to 16 shown in FIG. 4, the adsorption chamber 1performs the desorption operation, the adsorption chambers 2 to 5perform the condensation operation, the adsorption chambers 6 and 7perform the desorption operation, and the adsorption chamber 8 performsthe desorbed liquid collection operation.

In such a simulated moving bed, each of the supplying lines and thedrawing lines is moved by one adsorption chamber in a liquid flowingdirection through a bulb operation every predetermined time period.Accordingly, in the next arrangement state of the adsorption chambers,the adsorption chamber 2 performs the desorption operation, theadsorption chambers 3 to 6 perform the condensation operation, theadsorption chambers 7 and 8 perform the adsorption operation, and theadsorption chamber 1 performs the desorbed liquid collection operation.Such an operation is performed successively, whereby processing ofseparating the mixture of enantiomeric isomers can be continuously andefficiently achieved.

According to the production method of the present invention, there canbe provided an enantiomeric isomer-separating filler in which a porouscarrier is allowed to carry an optically active polymer compound in acarrying amount of 23 mass % or more. Furthermore, an enantiomericisomer-separating filler having a carrying amount of the opticallyactive polymer compound of about 60 mass % can be obtained depending onpurposes. From the viewpoint of the separating performance of theenantiomeric isomer-separating filler, the carrying amount of theoptically active polymer compound is adjusted to fall within the rangeof preferably 23 to 50 mass %, more preferably 23 to 40 mass %.

In particular, out of the production methods of the present invention, amethod in which the optically active polymer compound is carried on theporous carrier separately a plurality of times is applied, whereby anenantiomeric isomer-separating filler in which the porous carrier isallowed to carry a desired carrying amount of the optically activepolymer compound can be easily obtained.

The enantiomeric isomer-separating filler obtained by means of theproduction method of the present invention can be applied to anenantiomeric isomer analysis technology in which a wide variety ofchiral compounds are sampled with high productivity and subjected tooptical resolution in analysis of a pharmaceutical preparation, a food,an agricultural chemical, a perfume, or the like and to enantiomericisomer separation on an industrial scale utilizing a simulated movingbed mode, when it is preferably applied to pseudo-moving-bedchromatography.

EFFECT OF THE INVENTION

According to the production method of the present invention, there canbe provided an enantiomeric isomer-separating filler in which a porouscarrier is allowed to carry a polysaccharide derivative in a carryingamount of 23 mass % or more.

EXAMPLES

Hereinafter, the present invention will be described in detail by way ofexamples. However, the present invention is not limited to theseexamples. Details about a planetary stirring mixer used in examples areas follows.

-   -   Stirring blade: Two blades (They revolve while rotating        together, but their rotation directions are the same.)    -   Shape of stirring blade: Curved stirring rod (hook-shaped)    -   Revolution trajectory of stirring blade: Hypocycloid curve as        shown in FIG. 1    -   Capacity of stirring tank: 10 L for Example 3, 0.8 L for        examples other than Example 3    -   Rpm of stirring blade: 45 rpm for rotation, 23 rpm for        revolution Stirring time: 60 minutes

Example 1 Enantiomeric Isomer-Separating Filler Carrying amylosetris(3,5-dimethylphenylcarbamate))

(1) Synthesis of amylose tris(3,5-dimethylphenylcarbamate)

Under a nitrogen atmosphere, 100 g of amylose and 850 g of3,5-dimethylphenyl isocyanate were stirred in 4 L of dry pyridine underheating at 100° C. for 60 hours, and then the resultant was placed into60 L of methanol. The precipitated solid was filtered out and washedwith methanol, followed by vacuum drying (60° C., 15 hours). As aresult, 335 g of a yellowish white powdery solid was obtained (90%).

(2) Allowing Silica Gel to Carry amylosetris(3,5-dimethylphenylcarbamate)

87.5 g of amylose tris(3,5-dimethylphenylcarbamate) obtained in (1) weredissolved into 747 ml of ethyl acetate at 8.5 times equivalent (wt/vol)to prepare a dope, which was divided into 4 fractions.

Next, 162.5 g of silica gel subjected to surface inactivating treatment(average particle size: 20 μm, average pore size: 1,300 Å) were fed intothe planetary stirring mixer, and then a ¼ amount of the polymer dopewas placed into it.

Next, the planetary stirring mixer was actuated. The stirring conditionswere as the above. The stirring was performed at room temperature.

After the completion of the first stirring, the solvent (ethyl acetate)was distilled off under a reduced pressure condition while it washeated. Such a stirring operation was repeated 4 times to obtain atarget filler carrying amylose tris(3,5-dimethylphenylcarbamate).

(3) Preparation of Filling Column for HPLC from Prepared Filler

The filler carrying amylose tris(3,5-dimethylphenylcarbamate) preparedin (2) was filled in a stainless column having a length of 25 cm and aninner diameter of 0.46 cm (L/D=54.3) by means of a slurry filling methodto prepare a separating column for an enantiomeric isomer.

Example 2 Enantiomeric Isomer-Separating Filler Carrying amylosetris(3,5-dimethylphenylcarbamate)

(1) Synthesis of amylose tris(3,5-dimethylphenylcarbamate)

Amylose tris(3,5-dimethylphenylcarbamate) was prepared in the samemanner as in (1) of Example 1.

(2) Allowing Silica Gel to Carry Amylosetris(3,5-dimethylphenylcarbamate)

36 g of amylose tris(3,5-dimethylphenylcarbamate) obtained in (1) weredissolved into 277 ml (7.5 times equivalent (wt/vol)) of a mixed solventof chloroform and DMAc (vol/vol) to prepare a dope, which was dividedinto 4 fractions.

Next, 54 g of silica gel subjected to surface inactivating treatment(average particle size: 20 μm, average pore size: 1,300 Å) were fed intothe planetary stirring mixer, and then a ¼ amount of the polymer dopewas placed into it.

Next, the planetary stirring mixer was actuated. The stirring conditionswere as the above. The stirring was performed at room temperature.

After the completion of the first stirring, the solvent was distilledoff under a reduced pressure condition while it was heated. Such astirring operation was repeated 4 times to obtain a target fillercarrying amylose tris(3,5-dimethylphenylcarbamate).

(3) Preparation of Filling Column for HPLC from Prepared Filler

The filler carrying amylose tris(3,5-dimethylphenylcarbamate) preparedin (2) was filled in a stainless column having a length of 25 cm and aninner diameter of 0.46 cm by means of a slurry filling method to preparea separating column for an enantiomeric isomer.

Example 3 Enantiomeric Isomer-Separating Filler Carrying amylosetris(3,5-dimethylphenylcarbamate))

(1) Synthesis of amylose tris(3,5-dimethylphenylcarbamate)

Amylose tris(3,5-dimethylphenylcarbamate) was prepared in the samemanner as in (1) of Example 1.

(2) Allowing Silica Gel to Carry amylosetris(3,5-dimethylphenylcarbamate)

750 g of amylose tris(3,5-dimethylphenylcarbamate) obtained in (1) weredissolved into 6.6 L (8.8 times equivalent (wt/vol)) of a mixed solventof chloroform and DMAc (vol/vol) to prepare a dope, which was dividedinto 3 fractions.

Next, 1.75 kg of silica gel subjected to surface inactivating treatment(average particle size: 20 μm, average pore size: 1,300 Å) were fed intothe planetary stirring mixer, and then a ⅓ amount of the polymer dopewas placed into it.

Next, the planetary stirring mixer was actuated. The stirring conditionswere as the above. The stirring was performed at room temperature.

After the completion of the first stirring, the solvent was distilledoff under a reduced pressure condition while it was heated. Such astirring operation was repeated 3 times to obtain a target fillercarrying amylose tris(3,5-dimethylphenylcarbamate).

(3) Preparation of Filling Column for HPLC from Prepared Filler

The filler carrying amylose tris(3,5-dimethylphenylcarbamate) preparedin (2) was filled in a stainless column having a length of 25 cm and aninner diameter of 0.46 cm by means of a slurry filling method to preparea separating column for an enantiomeric isomer.

Example 4 Enantiomeric Isomer-Separating Filler Carrying amylosetris(3,5-dimethylphenylcarbamate))

(1) Synthesis of amylose tris(3,5-dimethylphenylcarbamate)

Amylose tris(3,5-dimethylphenylcarbamate) was prepared in the samemanner as in (1) of Example 1.

(2) Allowing Silica Gel to Carry amylosetris(3,5-dimethylphenylcarbamate)

12.5 g of amylose tris (3,5-dimethylphenylcarbamate) obtained in (1)were dissolved into 125 ml of ethyl acetate at 10 times equivalent(wt/vol) to prepare a dope, which was divided into 2 fractions.

Next, 37.5 g of silica gel subjected to surface inactivating treatment(average particle size: 20 μm, average pore size: 1,300 Å) were fed intothe planetary stirring mixer, and then a ½ amount of the polymer dopewas placed into it.

Next, the planetary stirring mixer was actuated. The stirring conditionswere as the above. The stirring was performed at room temperature.

After the completion of the first stirring, the solvent was distilledoff under a reduced pressure condition while it was heated. Such astirring operation was repeated one more time to obtain a target fillercarrying amylose tris (3,5-dimethylphenylcarbamate).

(3) Preparation of Filling Column for HPLC from Prepared Filler

The filler carrying amylose tris(3,5-dimethylphenylcarbamate) preparedin (2) was filled in a stainless column having a length of 25 cm and aninner diameter of 0.46 cm by means of a slurry filling method to preparea separating column for an enantiomeric isomer.

Comparative Example 1 Enantiomeric Isomer-Separating Filler Carryingamylose tris(3,5-dimethylphenylcarbamate))

(1) Synthesis of amylose tris(3,5-dimethylphenylcarbamate)

Amylose tris(3,5-dimethylphenylcarbamate) was prepared in the samemanner as in (1) of Example 1.

(2) Allowing Silica Gel to Carry amylosetris(3,5-dimethylphenylcarbamate)

2.5 g of amylose tris(3,5-dimethylphenylcarbamate) obtained in (1) weredissolved into 25 ml of ethyl acetate at 10 times equivalent (wt/vol).

A total amount of the polymer dope was added to 22.5 g of silica gelsubjected to surface inactivating treatment used in (2) of Example 1placed into a 300-ml three-necked flask, and the resultant was evenlyapplied by using a blade-type stirring rod.

After the application, the solvent was distilled off under a reducedpressure condition while it was heated, to thereby obtain a targetfiller carrying amylose tris(3,5-dimethylphenylcarbamate).

(3) Preparation of Filling Column for HPLC from Prepared Filler

The filler carrying amylose tris(3,5-dimethylphenylcarbamate) preparedin (2) was filled in a stainless column having a length of 25 cm and aninner diameter of 0.46 cm by means of a slurry filling method to preparea separating column for an enantiomeric isomer.

Comparative Example 2 Enantiomeric Isomer-Separating Filler Carryingamylose tris(3,5-dimethylphenylcarbamate))

(1) Synthesis of amylose tris(3,5-dimethylphenylcarbamate)

Amylose tris(3,5-dimethylphenylcarbamate) was prepared in the samemanner as in (1) of Example 1.

(2) Allowing Silica Gel to Carry amylosetris(3,5-dimethylphenylcarbamate)

20 g of amylose tris(3,5-dimethylphenylcarbamate) obtained in (1) weredissolved into 200 ml (10 times equivalent (wt/vol)) of a mixed solventof chloroform and DMAc (vol/vol) to prepare a dope, which was dividedinto 2 fractions.

Next, 80 g of silica gel subjected to surface inactivating treatment(average particle size: 20 μm, average pore size: 1,300 Å) were fed intothe planetary stirring mixer, and then a ½ amount of the polymer dopewas placed into it.

Next, the planetary stirring mixer was actuated. The stirring conditionswere as the above. The stirring was performed at room temperature.

After the completion of the first stirring, the solvent was distilledoff under a reduced pressure condition while it was heated. Such astirring operation was repeated twice to obtain a target filler carryingamylose tris (3,5-dimethylphenylcarbamate).

(3) Preparation of Filling Column for HPLC from Prepared Filler

The filler carrying amylose tris(3,5-dimethylphenylcarbamate) preparedin (2) was filled in a stainless column having a length of 25 cm and aninner diameter of 0.46 cm by means of a slurry filling method to preparea separating column for an enantiomeric isomer.

Comparative Example 3

(1) Synthesis of amylose tris (3,5-dimethylphenylcarbamate)

Amylose tris(3,5-dimethylphenylcarbamate) was prepared in the samemanner as in (1) of Example 1.

(2) Allowing Silica Gel to Carry amylosetris(3,5-dimethylphenylcarbamate)

20.0 g of amylose tris (3,5-dimethylphenylcarbamate) obtained in (1)were dissolved into 150 ml (7.5 times equivalent (wt/vol)) of ethylacetate to prepare a dope, which was divided into 4 fractions.

A ¼ amount of the polymer dope was added to 30.0 g of silica gelsubjected to surface inactivating treatment used in (2) of Example 1placed into a 300-ml three-necked flask, and the resultant was evenlyapplied by using a blade-type stirring rod. After that, the remainingpolymer dope (¾ amount) was placed (¼ amount per one placement: a totalof 3 times), and the resultant was evenly applied.

After the application, the solvent was distilled off under a reducedpressure condition while it was heated, to thereby obtain a targetfiller carrying amylose tris (3,5-dimethylphenylcarbamate) However, nocolumn was prepared because the amount of agglomerate was large.

Applied Example 1

50 μl of a solution (50 mg/ml) prepared by dissolving 50 mg of acompound I represented by the following formula into 1.0 ml of a mobilephase (ethanol) was charged into each of the separating columns forenantiomeric isomers prepared in Examples 1 to 5 and Comparative Example1, to thereby obtain chromatograms shown in FIGS. 5 to 10.

Furthermore, by using a continuous liquid preparative chromatographyapparatus of a small-simulated moving bed mode shown in FIG. 14, theadsorption chambers 1 to 8 were filled with the fillers prepared inExamples 1 to 5 and Comparative Examples 1 to 4, and the compound I wasactually separated under the following conditions, thereby determiningthe productivity of a raffinate component in each filler (expressed inthe mass (kg) of a racemic body that can be separated within a day per 1kg of the filler) Table 1 shows the results. All of the resultantoptical purities of the raffinate components were equal to or higherthan 97% ee.

<Preparative Separation Conditions>

-   -   Temperature: 25° C.    -   Mobile phase: Ethanol    -   Step time: 1.5 minutes    -   Feed concentration (concentration of the solution of the        compound (I) in ethanol): 50 mg/ml    -   Detection wavelength: 270 nm

Respective flow rates shown in Table 2 have the following meanings.

-   -   Feed flow rate: Flow rate of the solution of the compound (I) in        ethanol from the line 15    -   Raffinate flow rate: Flow rate in the line 16    -   Extract flow rate: Flow rate in the line 14

Desorbed liquid flow rate: Flow rate of ethanol from the line 13. TABLE1 Comparative Example Example 1 2 3 4 1 2 3 Carrying amount of 35 40 3025 10 20 40 polysaccharide derivative (mass %) Number of carrying 4 4 32 1 1 4 Feed flow rate 0.90 0.76 1.06 0.94 — 0.79 — (ml/min) Raffinateflow rate 15.31 20.99 10.87 7.49 — 6.73 — (ml/min) Extract flow rate5.33 8.61 5.11 3.56 — 3.43 — (ml/min) Desorbed liquid 19.74 28.83 14.9210.12 — 9.37 — flow rate (ml/min) Productivity 1.73 1.44 2.03 1.79 —1.51 —Productivity: kg-rac./kg-CSP/day,—: Unable to sample

1. A process for producing an enatiomeric isomer-separating filler,comprising bringing a porous carrier and a solution or dispersion of anoptically active polymer compound into contact with each other through astirring operation in a stirring device, to allow the porous carrier tocarry the optically active polymer compound, wherein: a two-axisvertical stirring device is used as the stirring device; and the porouscarrier is allowed to carry the optically active polymer compound in acarrying amount of 23 mass % or more.
 2. A method of producing anenantiomeric isomer-separating filler, comprising bringing a porouscarrier and a solution or dispersion of an optically active polymercompound into contact with each other through a stirring operation in astirring device, to allow the porous carrier to carry the opticallyactive polymer compound, wherein: a two-axis vertical stirring device isused as the stirring device; a first step involving: feeding the porouscarrier into the two-axis vertical stirring device; adding part of thesolution or dispersion of the optically active polymer compound with arequired amount being divided into multiple fractions; and allowing theporous carrier to carry the optically active polymer compound through astirring operation of the two-axis vertical stirring device, and asecond step involving drying the porous carrier carrying the opticallyactive polymer compound to remove a solvent are performed; and acombination of the first step and the second step is repeated aplurality of times by using a residual solution or dispersion of theoptically active polymer compound, to thereby allow the porous carrierto carry the optically active polymer compound.
 3. The method accordingto claim 2, wherein the combination of the first step and the secondstep is repeated 2 to 6 times.
 4. The method according to claim 1,wherein the porous carrier has an average particle size in a range of 1to 300 μm and an average pore size in a range of 200 to 8,000 Å.
 5. Themethod according to claim 1, wherein the optically active polymercompound comprises a polysaccharide derivative.
 6. The method accordingto claim 1, wherein the enantiomeric isomer-separating filler comprisesan enantiomeric isomer-separating filler for simulated moving bedchromatography.